Carbon Dioxide → (2S,5R)-1-allyl-2,5-dimethylpiperazine

Temperature

100 °C

A mixture of ethyl trans-2,5-dimethyl-1-piperazinecarboxylate (643 g, 3.45 mol), allyl bromide (328 mL, 3.80 mol), and sodium carbonate (440 g, 4.15 mol) in 2500 mL of acetonitrile was heated at reflux for 1.5 hours. The reaction was cooled to room temperature, filtered, and the solvent removed under vacuum. The residue was dissolved in 4000 mL of dichloromethane and washed with two 500 mL portions of 1M sodium hydroxide. The dichloromethane solution was dried over magnesium sulfate and the solvent was removed to give 630 g (81%) of ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate as an oil. Ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate (630 g, 2.78 mol) was added to a solution of 87% potassium hydroxide pellets (2970 g, 46 mol) in 4300 mL of 95% ethanol and heated at reflux for 1.5 hours. Carbon dioxide evolution was observed for the first 0.5-1 hour of heating. The reaction was cooled below reflux temperature and 2000 mL of toluene was carefully added. Ethanol was removed by azeotropic distillation at 105° C., while adding an additional 4000 mL of toluene to the reaction flask during the course of the distillation. After collection of 9000 mL of distillate, the reaction was cooled to 100° C. and 1000 mL of toluene was carefully added. The solution was slowly cooled to 5° C. and maintained at 5° C. for 30 minutes. The solution was filtered, and the filter cake was washed with an additional 1500 mL of toluene. The filtrate was washed with 1000 mL of water, dried over magnesium sulfate, and the solvent was removed to give 296 g (69%) of trans-1-allyl-2,5-dimethylpiperazine as a dark liquid. NMR (300 MHz, DMSO-d6): δ 0.87 (d, J=6.3 Hz, 3H); 0.92 (d, J=6.3 Hz, 3H); 1.63 (t, J=11 Hz, 1H); 2.05 (m, 1H); 2.30 (t, J=11 Hz, 1H); 2.6-2.8 (m, 4H); 3.33 (dd, J1 =5 Hz, J2 =14 Hz, 1H); 5.09 (d, J=8.7 Hz, 1H); 5.13 (d, J=14 Hz, 1H) 5.8 (m, 1H).

1. temperatureheated
2. temperatureat reflux for 1.5 hours
3. customwas observed for the first 0.5-1 hour
4. temperatureof heating
5. temperatureThe reaction was cooled
6. additionwas carefully added
7. customEthanol was removed by azeotropic distillation at 105° C.
8. additionwhile adding an additional 4000 mL of toluene to the reaction flask
9. distillationduring the course of the distillation
10. distillationAfter collection of 9000 mL of distillate
11. addition1000 mL of toluene was carefully added
12. temperatureThe solution was slowly cooled to 5° C.
13. temperaturemaintained at 5° C. for 30 minutes
14. filtrationThe solution was filtered
15. washthe filter cake was washed with an additional 1500 mL of toluene
16. washThe filtrate was washed with 1000 mL of water
17. dry with materialdried over magnesium sulfate
18. customthe solvent was removed

ORD record

ord-1717554f713649b59c1658ff850184d0

Source dataset

uspto-grants-1997_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05681830